DE3621026A1 - Novel complexes and complex salts - Google Patents

Abstract

Physiologically tolerable complex compounds of the general formula I <IMAGE> in which X denotes a hydrogen atom, a metal ion equivalent and/or a physiologically acceptable cation of an inorganic or organic base or amino acid, V<2> denotes a COOH or <IMAGE> group, in which R<6> stands for a straight- or branched-chain alkyl radical having 2 to 7 carbon atoms, which is optionally substituted by 1-5 hydroxyl groups, and R<7> stands for a hydrogen atom, a straight- or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms, which is substituted by 1 to 5 hydroxyl groups, V<2> denotes a COOX, <IMAGE> or COB group, where B denotes a protein or lipid radical, R<1> denotes a hydrogen atom or a CH2COOX group, R<2> and R<3> denote a (CH2)m group where m denotes 0 or 1 if R<4> and R<5> simultaneously in each case stand for a hydrogen atom, R<4> and R<5> denote a <IMAGE> group where m denotes 0 or 1, R<8> denotes a hydrogen atom or a U-R<9> group, where U stands for an oxygen, nitrogen or sulphur atom and R<9> stands for a -(CH2)p-C6H4-W-protein group where p denotes 1 or 2, W denotes -NH-, -NHCOCH2-, NHCS-, -OCH2CO-, -OCH2CONHNH-, -NHCH2CO-, -NHCH2CONHNH- or -OCH2CONH(CH2)nCO, where n stands for the figures 1 to 15 and -protein denotes a protein radical, if R<2> and R<3> simultaneously in each case stand for a hydrogen atom, where... Original abstract incomplete.

Description

The invention relates to new complexes and complex salts, these compounds containing agents, their use in diagnostics and methods for Manufacture of these compounds and agents.

Complexes or their salts have long been used in medicine, for. B. as an aid for the administration of poorly soluble ions (e.g. iron) and as antidotes (calcium or zinc complexes are preferred) for detoxification in the event of accidental incorporation of heavy metals or their radioactive ones Isotopes.

In the patents EP 71 564, EP 1 30 934 and DE-OS 34 01 052 are recently Complexes and complex salts as diagnostics, mainly as NMR diagnostics, been introduced.

All previously known complexes and their salts prepare in their clinical Application Compatibility and / or selectivity problems the bond and / or stability. These problems are all the more pronounced, ever higher the products derived from the complexing agents must be dosed. For example, in the treatment of metal poisoning limits the insufficient Kidney tolerance of the compounds available today and their tendency binding essential ions for the organism. The on and use of heavy elements as components of parenteral X-ray contrast media to be administered have so far failed due to the insufficient Compatibility of such connections. So far for magnetic resonance imaging proposed or tested paramagnetic, contrast-enhancing Substances is the distance between the effective and that in animal experiments toxic dose relatively narrow and / or they have a low organ specificity and / or stability and / or contrast-enhancing effect.  

There is therefore a need for a variety of purposes, especially for better tolerated, but also stable, readily soluble and sufficiently selective complex compounds.

It has now been found that complex compounds which result from the anion of a complexing acid and a central ion of an element of atomic numbers 21 to 29, 31, 32, 38, 39, 42 to 44, 49, 57 to 70 or 77 and optionally one or more physiologically acceptable cations of an inorganic and / or organic base or amino acid, surprisingly excellent are suitable for the production of diagnostic agents which are suitable for Suitable for use in NMR, X-ray, ultrasound or radio diagnostics.

They are described by the general formula I.

wherein
X is a hydrogen atom, a metal ion equivalent and / or a physiologically acceptable cation of an inorganic or organic base or amino acid,
V ¹ a

wherein
R ^{6 is} a straight-chain or branched-chain alkyl radical having 2 to 7 carbon atoms, which is optionally substituted by 1 to 5 hydroxyl groups, and
R ^{7 represents} a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups,
V ² a

where B is a protein or lipid residue,
R ^{1 is} a hydrogen atom or a CH ₂ COOX group,
R ² and R ^{3 are} a (CH ₂ ) _m group with m meaning 0 or 1, when R ⁴ and R ^{5 are} each a hydrogen atom,
R ⁴ and R ^{5 are} one

with m meaning 0 or 1,
R ^{8 has} the meaning of a hydrogen atom or a UR ^{9 group} ,
where U stands for an oxygen, nitrogen or sulfur atom and R ^{9 stands} for a group - (CH ₂ ) _p -C ₆ H ₄ -W protein with
p has the meaning of 1 or 2,
W in the meaning of -NN-, -NHCOCH ₂ -, -NHCS-, -OCH ₂ CO-, -OCH ₂ CONHNH-, -NHCH ₂ CO-, -NHCH ₂ CONHNH- or -OCH ₂ CONH (CH ₂ ) _n CO-, where n stands for the digits 1 to 15 and protein in the meaning of a protein residue,
when R ² and R ^{3 are} each a hydrogen atom, with the proviso that at least two of the substituents X are metal ion equivalents of an element of atomic numbers 21 to 29, 31, 32, 38, 39, 42 to 44, 49, 57- Are 70 or 77 and that when V ^{2 represents} a COB group, R ^{8 represents} a hydrogen atom.

The element of the above atomic number, which is the central ion of the forms physiologically compatible complex salt, can be aimed for The intended use of the diagnostic agent according to the invention, of course also be radioactive.

The agent according to the invention is intended for use in NMR diagnostics (see European Patent Application No. 71 564), the central ion of the Complex salt be paramagnetic. These are especially the two and trivalent ions of the elements of atomic numbers 21 to 29, 42, 44 and 57 to 70. Suitable ions are, for example, chromium (III) -, manganese (II) -, Iron (III) -, iron (II) -, cobalt (II) -, nickel (II) -, copper (II) -, Praseodymium (III), neodymium (III), samarium (III) and ytterbium (III) ion. Because of Because of their very strong magnetic moment, the gadolinium (III) -, Terbium (III) -, dysprosium (III) -, holmium (III) - and erbium (III) - ion.

Is the agent according to the invention for use in X-ray diagnostics determined, the central ion must differ from an element of higher atomic number derived in order to achieve sufficient absorption of the X-rays. It it has been found that for this purpose diagnostic agents which are a physiological compatible complex salt with central ions of elements of atomic numbers  contain between 57 and 70, are suitable; these are for example the lanthanum (III) ion and the above-mentioned ions of the lanthanide series.

Both the inventive agents for use in NMR diagnostics are intended, as well as those for use in X-ray diagnostics are suitable for use in ultrasound diagnostics.

For the use of the agents according to the invention in nuclear medicine Diagnostics, the central ion must be radioactive. For example, are suitable Radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, Strontium, technetium, indium, ytterbium, gadolinium and iridium.

The complex compounds according to the invention contain the amide groups

R ^{6 represents} a straight or branched chain, optionally mono- or polyhydroxylated hydrocarbon radical and R ^{7 represents} a hydrogen atom, a lower straight or branched chain optionally mono- or polyhydroxylated hydrocarbon radical. These radicals contain 2 to 7, preferably 2 to 4 carbon atoms and 1 to 5, preferably 2 to 4 hydroxyl groups. Examples of suitable hydroxyalkyl radicals are: 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) ethyl, 2,3-dihydroxypropyl, tris (hydroxymethyl) methyl, 2,3-dihydroxy-1-hydroxymethylpropyl, 2,3,4 , 5,6-pentahydroxyhexyl and preferably 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 2,3-dihydroxypropyl and 2,3,4-trihydroxybutyl.

If not all acidic hydrogen atoms of the acetic acid groups by the Central ion can be substituted, one, more or all remaining Hydrogen atom (s) by physiologically harmless cations of inorganic and / or organic bases or amino acids. Suitable inorganic Cations are, for example, the lithium ion, the potassium ion, the  Calcium ion and especially the sodium ion. Suitable organic cations Bases include those of primary, secondary or tertiary Amines such as ethanolamine, diethanolamine, morpholine, glucamine, N, N- Dimethylglucamine and especially N-methylglucamine. Suitable cations of Amino acids are, for example, those of lysine, arginine and ornithine.

The complex-forming acids can also be linked to biomolecules which are known to accumulate particularly in the organ or organ part to be examined. Such biomolecules are, for example, hormones, dextrans, bleomycins, insulin, prostaglandins, steroid hormones, amino sugars, amino acids, peptides such as polylysine, proteins (such as eg immunoglobulins and monoclonal antibodies) or lipids (also in the form of liposomes). Of particular note are conjugates with albumins such as human serum albumin, antibodies such as. B. monoclonal antibodies specific for tumor-associated antigens or antimyosin. Instead of the biomolecules, suitable synthetic polymers such as polyethyleneimines can also be attached. The diagnostic agents formed from this are suitable, for example, for use in tumor and infarct diagnostics. Particularly suitable monoclonal antibodies for conjugation are those which are directed against predominantly cell membrane-associated antigens. As such, monoclonal antibodies or their fragments (F (ab) ₂ ) are suitable for tumor imaging, for example. B. against the carcinoembryonic antigen (CEA), human choriogonadotropin (β-hCG) or other tumorigenic antigens, such as glycoproteins, are directed. Anti-myosin, anti-insulin and anti-fibrin antibodies are also suitable.

For example, are suitable for liver examinations or for tumor diagnosis Conjugates or inclusion compounds with liposomes (which, for example, as unilamellar or multilamellar phosphatidylcholine-cholesterol vesicles are used will).

The conjugate formation takes place either via a carboxyl group of the complex-forming acid or, in the case of the proteins or peptides, also via a (CH ₂ ) _p -C ₆ H ₄ -W- group as defined in claim 1. When the complex-forming acids are conjugated with proteins, peptides or lipids, several acid residues can be bound to the macromolecular biomolecule. In this case, each complex-forming acid residue can carry a central ion.

The coupling to the desired biomolecules is also carried out according to methods known per se, such as, for. B. in Rev. roum. Morphole. Embryo. Physiol., Physiologie 1981, 18, 241 and J. Pharm. Sci. 68, 79 (1979), for example by reaction of the nucleophilic group of a biomolecule, such as the amino, phenol, sulfhydryl, aldehyde or imidazole group, with an activated derivative of the complexing agent. Activated derivatives include, for example, monoanhydrides, acid chlorides, acid hydrazides, mixed anhydrides (see, for example, BGE Krejcarek and KL Tucker, Biochem., Biophys. Res. Commun. 1977, 581), activated esters, nitrenes or isothiocyanates. Conversely, it is also possible to implement an activated biomolecule with the complex-forming acid. For conjugation with proteins there are also substituents such. B. the structure C ₆ H ₄ N ₂ , C ₆ H ₄ NHCOCH ₂ , C ₆ H ₄ NHCS or C ₆ H ₄ OCH ₂ CO.

Serve as starting substances for the complex compounds according to the invention the compounds of the general formula Ia

wherein
V ¹ 'and V ² ' are the same or different and each have one

wherein
R ^{6 is} a straight-chain or branched-chain alkyl radical having 2 to 7 carbon atoms, which is optionally substituted by 1 to 5 hydroxyl groups, and
R ^{7 represents} a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups and which is substituted by 1 to 5 hydroxyl groups,
R ¹ ′ is a hydrogen atom or a CH ₂ COOH group,
R ² and R ^{3 are} a (CH ₂ ) _m group with m meaning 0 or 1, when R ⁴ 'and R ⁵ ' are each a hydrogen atom,
R ⁴ ′ and R ⁵ ′ are a CH ₂ -CH ₂ - (CH ₂ ) _m group with m in the meaning of 0 or 1 when R ³ and R ^{3 are} each a hydrogen atom,
means.

Educts for the preparation of these compounds are amines of the general Formula II

wherein
R ² , R ³ , R ⁴ 'and R ⁵ ' have the meaning given above. They are known from the literature (J. Pharm. Sci. 58, 1038 (1969) or are catalytically hydrogenated in a manner known per se, for example using rhodium / carbon or Nishimura contact as a catalyst (Houben-Weyl, methods of organic Chemistry, Vol. 4 / 1c, p. 256, Georg Thieme-Verlag, Stuttgart, New York 1980, F. Zymalkowsky, Catalytic Hydrogenation, Ferdinand Enke-Verlag Stuttgart 1965) from corresponding aromatic precursors (Rec. De Travau de Chim. Des Pays-Bas 72, 569 (1953), Ann. Chem. 537 (1978), J. Pharm. Soc. Japan 79, 549 (1959).

Subsequent alkylation with haloacetic acids or their esters of the formula HalCH ₂ COOR ¹⁰ , in which Hal represents chlorine, bromine or iodine and R ^{10 represents} a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, either gives the corresponding tetracarboxylic acid by choosing suitable auxiliary bases (R ¹ '= H) or their esters or the corresponding pentacarboxylic acid (R ¹ ' = CH ₂ COOH) or their esters.

Suitable auxiliary bases are all known to the person skilled in the art for alkylation reactions Bases such as alkali and alkaline earth carbonates, alkali and alkaline earth hydrogen carbonates, polymeric anion exchangers and the usual organic auxiliary bases such as B. triethylamine, tetramethylpiperidine, Pentamethylpiperidine, proton sponge and tetramethylguanidine. Preferred for the preparation of the tetraacetic acid-substituted compounds are lithium carbonate, Sodium carbonate and Amberlite LA2®, for the production of pentaacetic acid Residues bearing compounds potassium carbonate, tetra and pentamethyl piperidine.

Suitable solvents are all solvents which can be used for alkylations, preferably tetrahydrofuran, dimethylformamide, dimethylacetamide and Dimethyl sulfoxide.

The complexing agents of the general formula Ia with R ¹ 'in the meaning of a hydrogen atom, ie the tetraacetic acid-substituted compounds, can also by catalytic hydrogenation according to the above methods of the corresponding aromatic tetracarboxylic acids or their esters (Chem. Reports 117, 948 (1984 Subsequent N-alkylation in a manner known per se provides the desired pentaacetic acid-substituted complexing agents.

The necessary saponification of the acetic acid ester Groups are carried out according to the methods known to the person skilled in the art, for example with basic catalysts such as alkali or alkaline earth carbonates or hydroxides.

The introduction of amide groups for the preparation of compounds of the general formula Ia, in which V ¹ 'and / or V ² ' represent a CONR ⁶ R ⁷ group, is carried out by partial conversion of carboxyl groups of the aminotetra- and aminopentacarboxylic acids obtained in the manner described above in amide or mono- or polyhydroxyalkylamide groups. All synthesis possibilities known to the person skilled in the art are possible for this process. An example of this is the reaction of the anhydrides or esters of the general formulas III to V

R ^{11 has} the meaning of an alkyl radical having 1 to 4 carbon atoms,

wherein Y and Z together represent an oxygen atom or Y represents a hydroxyl group and Z represents the OR ^{11 group} , with mono- or polyhydroxyalkylamines of the general formula VI

where R ^{6 represents} a straight or branched chain optionally mono- or polyhydroxylated hydrocarbon radical and R ^{7 represents} a hydrogen atom, a lower straight or branched chain optionally mono- or polyhydroxylated hydrocarbon radical. These radicals contain 1 to 7, preferably 2 to 4 carbon atoms and 1 to 5, preferably 2 to 4 hydroxyl groups. Examples of suitable hydroxyalkyl radicals are: 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) ethyl, 2,3-dihydroxypropyl, tris (hydroxymethyl) methyl, 2,3-dihydroxy-1-hydroxymethylpropyl, 2,3, 4,5,6-pentahydroxyhexyl and preferably 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 2,3-dihydroxypropyl and 2,3,4-trihydroxybutyl.

The polyhydroxyalkylamines can advantageously also be in protected form used for the reaction, e.g. B. as O-acyl derivatives or as ketals. This applies particularly when these derivatives can be manufactured more conveniently and cheaply are than the polyhydroxyalkylamines themselves. A typical example is that 2-amino-1- (2,2-dimethyl-1,3-dioxolan-4-yl) ethanol, the acetonide of 1-amino 2,3,4-trihydroxybutans, prepared according to DE-OS 31 50 917.

The subsequent removal of the protective groups is easy and can, for. B. by treatment with an acidic ion exchanger in aqueous ethanol solution respectively.

The acid anhydrides of the general formula III can be prepared by known methods take place, for. B. according to the in US Patent 36 60 388 or in DE-OS 16 95 050 described procedure with acetic anhydride in pyridine.

In certain cases, however, it is particularly advantageous to eliminate water with carbodiimides in a suitable solvent, such as. B. Dimethylformamide or dimethylacetamide.

The preparation of the monoanhydrides of the formula V can, for example, according to the J.A.O.C.S. 59 (2) 105 (1982), see C.A. 96 164556 u (1982) Process carried out by partial hydrolysis of bis-anhydrides.

The conversion of the acid anhydrides to the hydroxyalkylamides according to the invention is carried out in the liquid phase. Suitable reaction media are, for example Water, dipolar aprotic solvents such as acetonitrile, N- Methylpyrrolidone, dimethylformamide, dimethylacetamide and the like or Mixtures of the same. The reaction temperatures are between approx. 0 ° C to 100 ° C, with temperatures of about 20 ° C to 80 ° C are preferred. The Response times are between 0.5 hours and 2 days, preferably between 1 hour and 36 hours.

The esters of the general formulas IV and V are prepared in  known manner, e.g. B. IV and V according to the in R. A. Guilmette et al., J. Pharm. Sci. 68, 194 (1979) and IV according to that described in U.S. Patent 3,497,535 Method.

The aminolysis of the esters takes place in the liquid phase, e.g. B. in a suitable higher-boiling solvents such as dimethylformamide, dimethylacetamide or Dimethyl sulfoxide. The reaction temperatures are around 20 ° C to 200 ° C, temperatures from 100 ° C to 180 ° C are preferred. The response times are between 2 hours and 2 days, with response times between 4 and 36 Hours are preferred.

In addition, all methods known to the person skilled in the art for converting Carboxyl groups in amide groups for the synthesis of the complexing agents according to the invention the general formula I are used, for. B. the method according to Krejcarek and Tucker, Biochem. Biophys. Res. Commun. 77, 581 (1977) mixed anhydrides.

The metal complexes according to the invention are prepared in the manner as it is disclosed in the patents EP 71 564, EP 1 30 934 and DE-OS 34 01 052 by using the metal oxide or a metal salt (e.g. that Nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21 to 29, 31, 32, 38, 39, 42 to 44, 49 or 57 to 70 in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) or suspended and with the solution or suspension of the equivalent amount of complexing acid of the general formula Ib  

wherein
V ¹ 'a

wherein
R ^{6 is} a straight-chain or branched-chain alkyl radical having 2 to 7 carbon atoms, which is optionally substituted by 1-5 hydroxyl groups and
R ^{7 represents} a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups,
V ² ″ a

where B is a protein or lipid residue,
R ¹ ′ is a hydrogen atom or a CH ₂ COOH group,
R ² and R ^{3 are} a (CH ₂ ) _m group with m in the meaning of 0 or 1, when R ⁴ and R ^{5 are} each a hydrogen atom, and then, if desired, acidic hydrogen atoms of acetic acid present -Groups, substituted by physiologically acceptable cations of inorganic and / or organic bases or amino acids, with the proviso that when V ² ″ stands for a -COB group, R ^{8 represents} a hydrogen atom, it is added to water and / or a lower alcohol and stir, if necessary, with heating or heating to the boiling point until the reaction is complete. If the complex salt formed is insoluble in the solvent used, it is isolated by filtration. If it is soluble, it can be isolated by evaporating the solution to dryness, for example by spray drying.

It is often the case that acidic groups are still present in the complex salt obtained expedient, the acidic complex salt by means of inorganic and / or organic Bases or amino acids that form physiologically harmless cations in to transfer neutral complex salts and isolate them. In many cases this is inevitable, since the dissociation of the complex salt by the Shift in pH to neutral is pushed back so far that this is the only way to isolate uniform products, or at least their cleaning is made possible.

The production is expediently carried out with the aid of organic bases or basic amino acids. The neutralization can also be carried out using inorganic Bases (hydroxides, carbonates or bicarbonates) of e.g. B. sodium, potassium or lithium.

To produce the neutral complex compounds, for example, the acidic complex salts in aqueous solution or suspension as much as desired Add bases so that the neutral point is reached. The solution obtained can then concentrated to dryness in vacuo. It is often an advantage the neutral salts formed by adding water-miscible Solvents, such as lower alcohols (methanol, ethanol, Isopropanol etc.), lower ketones (acetone etc.), polar ethers (tetrahydrofuran, Dioxane, 1,2-dimethoxyethane etc.) precipitate and so easy to isolate and to get easy-to-clean crystals. As special It has proven advantageous to have the desired base already during the Add complex formation of the reaction mixture and thereby a process step save.

If the acidic complex compounds contain several free acidic groups, then it often makes sense to produce neutral mixed salts that are both inorganic as well as organic physiologically harmless cations as counterions contain.

This can be done, for example, by adding the complexing acid to  aqueous suspension or solution with the oxide or salt of the central ion supplying element and half of the amount required for neutralization an organic base, the complex salt formed isolates it if desired, cleaned and then for complete neutralization with the required amount of inorganic base added. The order of base addition can also be reversed.

In the case of using radioisotopes containing complex compounds their manufacture according to the volume I in "Radiotracers for Medical Applications" CRC-Press, Boca Raton, Florida.

The diagnostic agents according to the invention are also produced in a manner known per se by using the complex compounds according to the invention optionally with the addition of the additives common in galenics suspended or dissolves aqueous medium and then the suspension or Solution sterilized if necessary. Suitable additives are, for example physiologically safe buffers (such as tromethamine), small additions of Complexing agents (such as diethylenetriamine-pentaacetic acid) or, if necessary, Electrolytes such as B. sodium chloride or, if necessary, antioxidants such as B. ascorbic acid.

Are suspensions or for enteral administration or other purposes Solutions of the agents according to the invention in water or physiological saline if desired, they are combined with one or more of the usual galenics Auxiliaries (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. Lecithins, Tweens®, Myrj®) and / or flavorings for flavor correction (e.g. essential oils) mixed.

In principle, it is also possible to use the diagnostic agents according to the invention can also be produced without isolating the complex salts. In any case, must be special Care should be taken to chelate so that the salts and salt solutions according to the invention are practically free from  complexed toxic metal ions.

This can be done, for example, with the help of color indicators such as xylenol orange Control titrations can be guaranteed during the manufacturing process. The invention therefore also relates to processes for the preparation of the complex compounds and their salts. The final security is cleaning the isolated complex salt.

Are suspensions of complex compounds for oral administration or other purposes in water or physiological saline, a sparingly soluble complex compound with one or more in galenics usual auxiliaries and / or surfactants and / or flavorings for flavor correction mixed.

The diagnostic agents according to the invention preferably contain 1 μmol to 1 Mol per liter of the complex salt and are usually in amounts of 0.001 dosed up to 5 mmol / kg. They are for enteral and parenteral administration certainly.

The complex compounds according to the invention are used

• 1.) for NMR, X-ray and ultrasound diagnostics in the form of their complexes with the ions of the elements with the atomic numbers 21 to 29, 42, 44 and 57 up to 70
• 2.) for radio diagnostics in the form of their complexes with the radioisotopes of Elements with atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 64, 70 and 77.

The agents according to the invention meet the diverse requirements for Suitability as a contrast medium for magnetic resonance imaging. So they are excellent suitable after oral or parenteral application by increasing the signal intensity in the image obtained with the aid of an MRI scanner to improve its informative value. Furthermore, they show the high effectiveness that is necessary to the body with the smallest possible amounts of foreign substances strain, and the good tolerance that is necessary to the non-invasive  To maintain the character of the investigations (which are described in J. Comput. Tomography 5, 6: 543-46 (1981), in Radiology 144, 343 (1982) and in Brevet Special de Medicament No. 484 M (1960) are examples of compounds too toxic).

The good water solubility of the agents according to the invention allows highly concentrated Manufacture solutions so that the volume load of the circuit in keep reasonable limits and dilution by body fluid balance, d. H. NMR diagnostics must be 100 to 1000 times more water-soluble than for NMR spectroscopy. Furthermore, the invention Not only a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the toxic ions within the complexes that are not covalently bound within the time when the new contrast agents are completely excreted are done extremely slowly. For example, for tumor diagnosis conjugates with proteins and antibodies already used a surprisingly high signal amplification in such a low dose that solutions of a correspondingly low concentration are used here can be.

In general, the agents according to the invention are used for use as NMR Diagnostics in amounts of 0.001 to mmol / kg, preferably 0.005 to 0.5 doses of mmol / kg. Details of the application are e.g. B. in H. J. Weinmann et al., At the. J. of Roentgenology 142, 619 (1984).

In contrast to conventional X-ray diagnostics with shadowing X-ray contrast media exists in NMR diagnostics with paramagnetic contrast agents no linear dependence of the signal amplification on the applied one Concentration. As control examinations show, an increase leads the dose applied does not necessarily result in signal amplification and it can with a high dose of paramagnetic contrast medium even to one Cancellation of the signal come. It was therefore surprising that some pathological processes only after application of higher doses strongly paramagnetic contrast medium according to the invention become visible. So  can e.g. B. the detection of a defective blood-brain barrier in the area of cranial abscess only after administration of 0.05-2.5 mmol / kg, preferably 0.1- 0.5 mmol / kg, of paramagnetic complex salts such as e.g. B. Gadolinium-2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid in the form of its good water-soluble salts. For a dose greater than 0.1 mmol / kg are solutions of higher concentrations up to 1 mol / l, preferably 0.25 to 0.75 mol / l required, as this is the only way to reduce the volume load and the Handling of the injection solution is guaranteed.

Particularly low doses (below 1 mg / kg) of organ-specific NMR diagnostics are z. B. for the detection of tumors and heart attacks.

The agents according to the invention are outstandingly suitable as X-ray contrast agents, it should be emphasized that there is no sign of them the anaphylaxis-like reactions known from iodine-containing contrast media can be identified in biochemical-pharmacological studies. Especially They are valuable because of the favorable absorption properties in areas higher tube voltages for digital subtraction techniques.

In general, the agents according to the invention for use as X-ray contrast media in analogy to z. B. Meglumine diatrizoate in amounts of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg dosed.

Details of the use of X-ray contrast media are e.g. B. in bark, X-ray contrast medium, G. Thieme, Leipzig 1970 and P. Thurn, E. Bücheler "Introduction to X-ray Diagnostics", G. Thieme, Stuttgart, New York 1977 discussed.

The means according to the invention are - since their acoustic impedance is higher than that of body fluids and tissues - also as a contrast medium for Suitable for ultrasound diagnostics, especially in the form of suspensions. They are generally used in amounts of 0.1 to 5 mmol / kg, preferably of 0.25 to 1 mmol / kg, metered.  

Details of the use of ultrasound diagnostics are e.g. B. in T. B. Tyler et al., Ultrasonic Imaging 3,323 (1981), J.I. Haft, "Clinical Echocardiography", Futura, Mount Kisco, New York 1978 and G. Stefan "Echocardiography" G. Thieme Stuttgart / New York 1981.

The agents according to the invention are due to their favorable radioactive properties and the good stability of the complex compounds contained in them also suitable as radio diagnostics.

Details of their application and dosage are e.g. B. in "Radiotracers for Medical Applications ", CRC Press, Boca Raton, Florida.

The following is the preparation of starting substances of the general Formula Ia described  

2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid

31.6 g (55.0 mmol) of 2,6-bis [N, N-bis (ethoxycarbonylmethyl) aminomethyl] - 1-piperidine acetic acid ethyl ester are in 160 ml Dioxane dissolved and the solution diluted with 160 ml of water. Add to this solution with stirring and slow heating 30.6 ml of 11 normal sodium hydroxide solution were added dropwise to 80 ° C. It is held at 80 ° C for 1.5 hours and after cooling Adjusted to pH 2 with concentrated hydrochloric acid at 20 ° C. The acidic solution is on a cation exchanger Type Amberlite® IR 120 given, the exchanger with plenty Washed water and then with semi-concentrated Ammonia elutes. The one obtained by evaporating the eluate The crude product is again dissolved in 400 ml of water and thoroughly Addition of IR 120 adjusted to pH 2.6. The exchanger is suction filtered and the aqueous solution evaporated. The residue (18.1 g) is dissolved in 170 ml of methanol and 10 ml Dissolved water with heating and slowly cooled. 13.8 g of colorless crystals (57% of theory) are obtained. melting point 189-191 ° C.

Analysis:

C 47.11 H 6.28 N 9.70 (calc.)
C 47.02 H 6.30 N 9.64 (found)

The starting material is produced in the following way:  

a) 2,6-bis (aminomethyl) piperidine trihydrochloride

123.3 g (0.5 mol) of 2,6-bis (aminoethyl) pyridine trihydrochloride (Annalen der Chemie 537-544 (1978)) are dissolved in 2.5 ml Dissolved water and with the addition of 25 g rhodium / coal as Catalyst in an autoclave at a maximum of 50 ° C and 16 bar initial pressure hydrogenated within 1 hour. The catalyst will filtered off and the colorless filtrate to dryness in vacuo constricted. The oily residue is in 1250 ml of methanol dissolved with heating and then evaporated again. The foam obtained is successively only in 600 ml of methanol and then stirred in 600 ml of acetonitrile at 25 ° C, filtered and dried in vacuo. 109 g (86% of theory) are obtained. a colorless, highly hygroscopic powder of melting point 263 to 264 ° C.

Analysis:

C 33.28 H 7.98 N 16.64 Cl 42.10 (calc.)
C 33.31 H 7.91 N 16.50 Cl 42.13 (found)

b) 2,6-bis [N, N-bis (ethoxycarbonylmethyl) aminomethyl] -1- piperidine acetic acid ethyl ester

50.52 g (200 mmol) of 2,6-bis (aminomethyl) piperidine trihydrochloride are in 1200 ml of dimethylacetamide with stirring 165.8 g (1.2 mol) of potassium carbonate were added. After encore of 167 ml (1.5 mol) of ethyl bromoacetate is used for 24 hours heated to 100 ° C. After cooling to 25 ° C, the mixture is filtered and the filtrate was concentrated in vacuo. You get as residue a low viscosity oil that is absorbed in 1200 ml of ethyl acetate becomes. The organic phase is washed 4 times with 300 ml each Water, dries over sodium sulfate, filtered and concentrated the filtrate in a vacuum. You get a raw product, the  via column chromatography (material: silica gel) with methylene chloride / Methanol (95: 5) is cleaned as the eluent. 78 g (68% of theory) of light oil are obtained, the Purity is determined by gas chromatography.

Analysis:

C 56.53 H 8.26 N 7.32 (calc.)
C 56.44 H 8.12 N 7.39 (found)

2,6-bis [N, N-bis (carboxymethyl) aminomethyl] piperidine

28.4 g (50 mmol) of 2,6-bis [N, N-bis (ethoxycarbonylmethyl) aminomethyl] -1-piperidine hydrobromide in 200 ml of dioxane / Water (1: 1) dissolved.

With stirring and heating to 80 ° C, 27 ml of 11 normal Sodium hydroxide solution added dropwise and the solution at 80 ° C. for 1.5 hours held. After cooling to room temperature, it is concentrated Acidified hydrochloric acid to pH 2 and the acidic solution on an amberlite IR 120 cation exchanger given. The exchanger is washed with plenty of water and then eluted with semi-concentrated ammonia. Evaporation of the eluate gives a crude product, which is dissolved again in 300 ml of water. Subsequently the solution is adjusted to pH 3.0 with IR 120. The exchanger is suctioned off and the solution is concentrated in vacuo. The residue is recrystallized from methanol / water (10: 1). 13.5 g (72% of theory) of a colorless product are obtained Crystals from melting point 129 to 132 ° C.

Analysis:

C 48.00 H 6.71 N 11.19 (calc.)
C 47.78 H 6.97 N 11.02 (found)

The starting material is produced in the following way:

a) 2,6-bis [N, N-bis (ethoxycarbonylmethyl) aminomethyl] -1- piperidine hydrobromide

25.2 g (100 mmol) of 2,6-bis (aminomethyl) piperidine trihydrochloride (prepared according to Example 1a) in 600 ml of dimethylacetamide suspended and with 61.1 ml (550 mmol) of ethyl bromoacetate and 410 ml (900 mEquiv) liquid anion exchanger Amberlite LA 2 offset. It will be open 24 hours Heated 60 ° C, after cooling to 25 ° C the solvent removed and the oily residue is stirred with 2 l of n-pentane. A colorless precipitate is obtained, which after filtration washed several times with n-pentane and then in vacuo is dried at 40 ° C. 38.9 g of a crude product are obtained, which is recrystallized from 400 ml of ethyl acetate. Man receives 31 g (55% of theory) of colorless crystals of Melting point 116 to 117 ° C.

Analysis:

C 48.49 H 7.45 N 7.39 Br 14.06 (Ber.)
C 48.80 H 7.51 N 7.20 Br 13.81 (found)

The desired tetraester (hydrobromide) can be same way using lithium or sodium carbonate as an auxiliary base.  

2,6-bis [N, N-carboxymethyl-N- (2,3-dihydroxy-N-methylpropyl- carbamoylmethyl) aminomethyl] -1-piperidine acetic acid

4.0 g (10 mmol) of 2,6-bis (2,6-dioxomorpholino-methyl) -1-piperidine acetic acid, dissolved in 50 ml of dry N-methylpyrrolidone with 2.1 g (20 mmol) of N-methylaminopropane-2,3-diol transferred. The solution is heated to 60 ° C. for 5 hours, stir for 16 hours at room temperature and remove that Solvent in a vacuum. The residue is stirred in 100 ml of diethyl ether. A colorless precipitate is obtained, which is filtered off and dried in vacuo. You get 4.6 g (76% of theory) of a white powder of melting point 104 to 108 ° C.

Analysis:

C 49.42 H 7.47 N 11.53 (calc.)
C 49.27 H 7.19 N 11.67 (found)

The starting material is produced in the following way:

a) 2,6-bis (2,6-dioxomorpholino-methyl) -1-piperidine acetic acid

4.3 g (10 mmol) of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid (prepared according to Example 1) are dissolved in 80 ml of dimethylformamide with heating and the solution is then heated to 5 ° C. chilled. 4.2 g (20 mmol) of dicyclohexylcarbodiimide, solid, are added with stirring and cooling. Upon further cooling for 12 hours, the resulting dicyclohexylurea separates out as a white, voluminous precipitate. It is filtered and the filtrate in vacuo at max. Concentrated at 50 ° C. A light yellow oil is obtained, from which the desired anhydride can be precipitated by stirring with various organic solvents, preferably with organic ethers such as diethyl ether. A white powder is obtained which, however, hydrolyzes in air. The desired anhydride is therefore detected in the dimethylformamide solution by IR spectroscopy (anhydride bands at 1820 and 1780 cm ^-1 and COOH at 1640 cm ^-1 ), the solution is concentrated in vacuo and the residue is reacted with the hydroxyalkylamines in the desired amount Solvent, preferably in N-methyl-2-pyrrolidone.

2,6-bis {N-carboxymethyl-N- [bis (2-hydroxyethyl) carbamoylmethyl] - aminomethyl} -1-piperidine acetic acid

9.9 g (25 mmol) of 2,6-bis (2,6-dioxomorpholinomethyl) -1-piperidine acetic acid (prepared according to Example 3) dissolved in 150 ml of dry dimethylformamide, 5.25 g (50 mmol) of diethanolamine are added and the solution heated to 50 ° C for 5 hours. You stir 16 Hours at room temperature and removes the solvent in a vacuum. The residue is stirred with 150 ml of diisopropyl ether, whereby a colorless precipitate is obtained. To Filtration and drying in vacuo gives 12.2 g (82% of theory) of a colorless powder with a melting point of 141 up to 146 ° C.

Analysis:

C 49.42 H 7.46 N 11.53 (calc.)
C 49.70 H 7.32 N 11.41 (found)

2,6-bis [N-carboxymethyl-N- (2.3.4-trihydroxybutylcarbamoylmethyl) - aminomethyl] -1-piperidine acetic acid

4.0 g (10 mmol) of 2,6-bis (2,6-dioxomorpholinomethyl) -1-piperidine acetic acid (prepared according to Example 3) dissolved in 50 ml dry N-methylpyrrolidone, with 3.2 g (20 mmol) 2-Amino-1- (2,2-dimethyl-1,3-dioxolan-4-yl) ethanol added and heated to 60 ° C for 4 hours. Then stir 16 Hours at room temperature after, the solvent is removed in vacuo and the residue is stirred in 150 ml of diisopropyl ether. The precipitate is filtered and in 150 ml of water added. You acidify with concentrated Hydrochloric acid to pH 1, stirred overnight at room temperature and constricts in a vacuum. The residue is dissolved several times in diisopropyl ether stirred, filtered and dried in vacuo. 4.3 g (68% of theory) of a colorless product are obtained Powder with a melting point of 112 to 115 ° C.

Analysis:

C 46.94 H 7.09 N 10.95 (calc.)
C 46.71 H 7.18 N 11.10 (found)

The following exemplary embodiments serve to further explain the invention.

example 1 Gadolinium III complex of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1- piperidine acetic acid

43.3 g (100 mmol) of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1piperidine acetic acid are suspended in 300 ml of water and with 18.13 g (50 mmol) Gadolinium oxide added. The mixture is heated at 100 ° C. for 3 hours, filtered and concentrated the filtrate in a vacuum. The residue is dried in vacuo at 60 ° C. 58.1 g (99% of theory) of a white powder, the melting point of which is obtained is above 320 ° C.

Analysis:

C 34.75 H 4.12 N 7.15 Gd 26.76 (calc.)
C 34.62 H 4.27 N 7.29 Gd 26.32 (found)

In an analogous manner, by reacting the complexing agent with gadolinium 153-chloride the corresponding radioactive complex.

In an analogous manner, by reacting the complexing agent with indium 111-chloride (5 mCi / 0.1 ml) the corresponding indium-111 complex.  

Example 2 Mono-N-methylglucamine salt of the gadolinium III complex of the 2,6-bis [N, N-bis- (carboxymethyl) aminomethyl] -1-piperidine acetic acid

8.67 g (20 mmol) of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1piperidine acetic acid are suspended in 50 ml of water and with 3.62 g (10 mmol) of gadolinium oxide transferred. The mixture is heated to 100 ° C. and 3.90 g (20 mmol) are added after 15 minutes. N-methylglucamine too. It is kept at 100 ° C for 2 hours, from one filtered slight turbidity and the filtrate was concentrated in vacuo. The residue is dried in vacuo at 60 ° C. 15.25 g (97% of the Theory) of a white powder with a melting point of 185 to 190 ° C.

Analysis:

C 36.82 H 5.28 N 7.16 Gd 20.09 (calc.)
C 37.01 H 5.02 N 7.01 Gd 19.85 (found)

Example 3 N-methylglucamine salt of the gadolinium III complex of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] piperidine

A suspension of 1.78 g (4.7 mmol) of 2,6-bis- [N, N-bis (carboxymethyl) aminomethyl]  piperidine and 0.85 g (2.35 mmol) of gadolinium oxide in 5 ml of water are 2 hours heated to 80 ° C, with continuous addition of 0.92 g (4.7 mmol) D - (-) - N- Methylglucamine the pH rose to 7.5. Then was over a G4 glass frit aspirated and the solution on a rotary evaporator in a water jet pump vacuum evaporated and the residue dried at 50 ° C and 0.1 Torr. You get 3.06 g (89% of theory) of a white powder with a melting point of 242-244 ° C.

Analysis:

C 36.46 H 5.63 N 7.73 Gd 21.70 (calc.)
C 36.04 H 5.49 N 7.62 Gd 20.93 (found)

Example 4 Gadolinium complex of 2,6-bis [N, N-carboxymethyl-N- (2,3-dihydroxy-N-methylpropylcarbamoylmethyl) - -aminomethyl] -1-piperidine acetic acid

15.2 g (25 mmol) of 2,6-bis [N-carboxymethyl-N- (2,3-dihydroxy-Nmethylpropylcarbamoylmethyl) - aminomethyl] -1-piperidine acetic acid are dissolved in 100 ml of water and 8.4 g (25 mmol) of anhydrous gadolinium acetate were added. Stir 3 Hours at room temperature and first gives the solution through an anion exchanger Amberlite® IRA 410 and then the aqueous eluate through a cation exchanger Amberlite® IRC 50. It is again eluted with water and the eluate concentrated in vacuo. After drying the residue, 13.6 g are obtained (71% of theory) of a colorless powder with a melting point of 218 to 220 ° C.

Analysis:

C 39.41 H 5.56 N 9.19 Gd 20.64 (calc.)
C 39.17 H 5.70 N 9.27 Gd 20.50 (found)

Example 5 Gadolinium complex of 2,6-bis {N-carboxymethyl-N- [bis- (2-hydroxyethyl) carbamoyl] - aminomethyl} -1-piperidine acetic acid

7.6 g (12.5 mmol) of 2,6-bis {N-carboxymethyl-N- [bis- (2-hydroxyethyl) carbamoylmethyl] - aminoethyl} -1-piperidine acetic acid are dissolved in 70 ml of water and treated with 4.2 g (12.5 mmol) of anhydrous gadolinium acetate. After 4 hours The solution is stirred at room temperature using an Amberlite® anion exchanger IRA 410 given. You elute with water and pour the eluate onto you Cation exchanger Amberlite® IRC 50. The aqueous eluate is in a vacuum concentrated and the residue dried. 6.9 g (73% of theory) are obtained. a colorless powder with a melting point of 212 to 216 ° C.

Analysis:

C 39.41 H 5.56 N 9.19 Gd 20.64 (calc.)
C 39.26 H 5.40 N 9.01 Gd 20.87 (found)

Example 6 Gadolinium complex of 2,6-bis [N-carboxymethyl-N- (2,3,4-trihydroxybutylcarbamoylmethyl) - aminomethyl] -1-piperidine acetic acid

18.0 g (25 mmol) of 2,6-bis [N-carboxymethyl-N- (2,3,4-trihydroxybutylcarbamoylmethyl) - aminomethyl] -1-piperidine acetic acid are dissolved in 150 ml of water and 8.4 g (25 mmol) of anhydrous gadolinium acetate were added. You stir 4 Hours at room temperature, the solution first gives an anion and then on a cation exchanger as described in Examples 4 and 5 and the eluate is concentrated in vacuo. After drying, 15.3 g (70% of the Theory) of a colorless powder with a melting point of 240 to 242 ° C.

Analysis:

C 37.82 H 5.33 N 8.82 Gd 19.81 (calc.)
C 37.69 H 5.56 N 8.96 Gd 19.62 (found)

Example 7 Preparation of a solution of the di-N-methylglucamine salt of gadolinium III Complex of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1piperidine acetic acid

58.76 g (0.1 mol) of the gadolinium III complex obtained in Example 1 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid are described in 40 ml water p. i. suspended. After adding 0.18 g of tromethamine hydrochloride and 39.1 g (0.2 mol) of N-methylglucamine is dissolved neutral, the solution with Water p. i. made up to 100 ml, filled into ampoules and heat sterilized.

Example 8 Preparation of a solution of the di-lysine salt of the Gadolinium III complex 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid

293.8 g (0.5 mol) of the gadolinium III complex of the 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid in 500 ml of water p. i. suspended. 292.4 g (1 mol) of lysine are added and the mixture is left under mild stirring for several hours Stir warm and then fill with water p. i. ad 1000 ml. The solution will be bottled and heat sterilized.  

Example 9 Preparation of a solution of the sodium salt of the gadolinium III complex 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid

587.64 g (1 mol) of the gadolinium III complex of the 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid in 500 ml of water p. i. suspended and neutral by adding 40 g (1 mol) caustic soda in portions solved. After adding 1.5 g of tromethamine, the solution is washed with water p. i. ad Filled up, filled into bottles and heat sterilized.

Example 10 Preparation of a solution of the gadolinium III complex from the conjugate of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid with human serum albumin

To 20 ml of a solution of 3 mg of the protein in 0.05 molar sodium bicarbonate buffer (pH 7-8) 10 mg of 2,6-bis (2,6-dioxomorpholino-methyl) -1-piperidine acetic acid, dissolved in 0.1 ml of dimethylformamide, added. Allow 30 minutes Stir at room temperature and then dialyze against a 0.3 molar Sodium phosphate buffer. Then add 50 mg of gadolinium III acetate and purifies by gel chromatography on a Sephadex G25 column. The received The fraction is sterile filtered and filled into multivials. By freeze drying a storable dry preparation is obtained.

In an analogous manner, the solution of the corresponding one is obtained with immunoglobulin Complex conjugates.  

Example 11 Preparation of with Gadolinium-III-2,6-Bis [N, N-bis (carboxymethyl) aminomethyl] - 1-piperidine acetic acid-loaded liposomes

According to the in Proc. Natl. Acad. Sci. U.S.A. 75, 4194 becomes a lipid mixture of 75 mol% egg. Phosphatidylcholine and 25 mol% Cholesterol produced as a dry substance. 500 mg in 30 ml Dissolved diethyl ether and dropwise in the ultrasonic bath with 3 ml of a 0.1 molar solution of the di-N-methylglucamine salt of the gadolinium III complex 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid in water p. i. transferred. After the solution has been added completely, the ultrasound is placed 10 minutes away and then concentrated in the Rotavapor. The gel-like Residue is suspended in 0.125 molar sodium chloride solution and at 0 ° C repeated by centrifuging (20,000 g / 20 minutes) non-encapsulated Free contrast medium. Then the liposomes thus obtained Freeze-dried in a multivial. The application takes place as colloidal Dispersion in 0.9% saline by weight.  

Example 12 Preparation of a solution of the yttrium-90 complex from the conjugate of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid with monoclonal antibody

To 1 ml of a solution of 0.15 mg monoclonal antibody (with specificity against melanoma antigen) in 0.05 molar sodium bicarbonate buffer (pH 7-8) 1 mg 2,6-bis (2,6-dioxomorpholino-methyl) - 1-piperidine acetic acid, dissolved in 0.01 ml of dimethylformamide, is added. The mixture is stirred for 30 minutes at room temperature and dialyzed against a 0.3 molar sodium phosphate buffer. Then 250 μl of a ⁹⁰ Y solution in acetate buffer (pH 6; produced according to Int. J. Appl. Radiat. Isot. Vol. 36 (1985), p. 803) are added and incubated for 15 minutes at room temperature. The solution is passed through a combined Sephadex G25 column and the radioactive protein fraction is sterile filtered and filled into multivials. A storable dry preparation is obtained by lyophilization.

Claims (15)

1. Physiologically compatible complex compounds of the general formula I wherein
X is a hydrogen atom, a metal ion equivalent and / or a physiological
harmless cation of an inorganic or organic base or amino acid,
V ¹ a wherein
R ^{6 is} a straight-chain or branched-chain alkyl radical having 2 to 7 carbon atoms, which is optionally substituted by 1 to 5 hydroxyl groups, and
R ^{7 represents} a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups,
V ² a where B is a protein or lipid residue,
R ^{1 is} a hydrogen atom or a CH ₂ COOX group,
R ² and R ^{3 are} a (CH ₂ ) _m group with m meaning 0 or 1, when R ⁴ and R ^{5 are} each a hydrogen atom,
R ⁴ and R ^{5 are} one with m meaning 0 or 1,
R ^{8 has} the meaning of a hydrogen atom or a UR ^{9 group} , where U represents an oxygen, nitrogen or sulfur atom and R ^{9 represents} a group - (CH ₂ ) _p -C ₆ H ₄ -W protein
p has the meaning of 1 or 2,
W in the meaning of -NN-, -NHCOCH ₂ -, -NHCS-, -OCH ₂ CO-, -OCH ₂ CONHNH-, -NHCH ₂ CO-, -NHCH ₂ CONHNH- or -OCH ₂ CONH (CH ₂ ) _n CO-, where n stands for the digits 1 to 15 and protein in the meaning of a protein residue,
when simultaneously R ² and R ³ each represent a hydrogen atom, with the proviso that at least two of the substituents X metal ion equivalents of an element of atomic numbers 21 to 29, 31, 32, 38, 39, 42 to 44, 49, 57 to Are 70 or 77 and that when V ^{2 represents} a COB group, R ^{8 represents} a hydrogen atom. 2. Physiologically compatible complex compounds according to claim 1, characterized characterized in that at least two of the substituents X metal ion equivalents an element of atomic numbers 21 to 29, 42, 44 or 57 to 70 are. 3. Physiologically compatible complex compounds according to claim 1, characterized characterized in that at least two of the substituents X metal ion equivalents a radionuclide of an element of atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 64, 70 or 77. 4. Physiologically compatible complex compounds according to claim 1, characterized in that V ¹ and V ² each for one stand. 5. Physiologically compatible complex compounds according to claim 1, characterized in that V ¹ and V ² each represent a COOX group. 6. Physiologically compatible complex compounds according to claim 1, characterized in that V ^{2 is} a COB group. 7. Physiologically compatible complex compounds according to claim 1, characterized in that R ^{1 represents} a hydrogen atom. 8. Physiologically compatible complex compounds according to claim 1, characterized in that R ^{1 represents} a CH ₂ COOX group. 9. Physiologically compatible complex compounds according to claim 1, characterized in that R ² and R ^{3 are} a (CH ₂ ) _m group and simultaneously R ⁴ and R ⁵ each represent a hydrogen atom. 10. Physiologically compatible complex compounds according to claim 1, characterized in that
R ⁴ and R ^{5 are} one are and simultaneously R ² and R ³ each represent a hydrogen atom. 11. Diagnostic agents containing at least one physiologically tolerable Complex compound according to claim 1 to 10, optionally with those in the Galenik usual additives. 12. Use of at least one physiologically compatible complex compound according to claims 2 to 10 for the preparation of agents for the NMR, X-ray or ultrasound diagnostics. 13. Use of at least one physiologically compatible complex compound according to claims 3 to 10 for the preparation of agents for the radio Diagnosis.   14. A process for the preparation of physiologically compatible complex compounds according to claim 1, characterized in that the metal oxide or metal salt of an element of atomic numbers 21 to 29, 31, 32, 38, 39, 42 to 44, 49, 57 to in a manner known per se 70 or 77 of a complexing acid of the general formula Ib wherein
V ¹ 'a wherein
R ^{6 is} a straight-chain or branched-chain alkyl radical having 2 to 7 carbon atoms, which is optionally substituted by 1-5 hydroxyl groups and
R ^{7 represents} a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups,
V ² ″ a where B is a protein or lipid residue,
R ¹ ′ is a hydrogen atom or a CH ₂ COOH group,
R ² and R ^{3 are} a (CH ₂ ) _m group with m meaning 0 or 1, when R ⁴ and R ^{5 are} each a hydrogen atom,
R ⁴ and R ^{5 are} one with m meaning 0 or 1
R ^{8 has} the meaning of a hydrogen atom or a UR ^{9 group} , where U represents an oxygen, nitrogen or sulfur atom and R ^{9 represents} a group - (CH ₂ ) _p -C ₆ H ₄ -W protein
p has the meaning of 1 or 2,
W in the meaning of -NN-, -NHCOCH ₂ -, -NHCS-, -OCH ₂ CO-, -OCH ₂ CONHNH-, -NHCH ₂ CO-, -NHCH ₂ CONHNH- or OCH ₂ CONH (CH ₂ ) _n CO-, where n stands for the digits 1 to 15 and -protein in the meaning of a protein residue, when R ² and R ³ each simultaneously represent a hydrogen atom, and then, if desired, acidic hydrogen atoms of acetic acid groups present , substituted by physiologically harmless cations of inorganic and / or organic bases or amino acids,
with the proviso that when V ^{2 ″ represents} a -COB group, R ^{8 represents} a hydrogen atom. 15. A method for producing the diagnostic agent according to claim 11, characterized in that the in water or physiological Saline solution dissolved or suspended complex compound, optionally with the additives customary in galenics in one for enteral or parenteral application brings appropriate form.